Interleukin-15 receptor complex (IL-15R) (IL-15R)

The Interleukin-15 receptor complex (IL-15R) is a heterotrimeric type I cytokine receptor that plays a pivotal role in the development, survival, and activation of natural killer (NK) cells and memory CD8+ T lymphocytes [3, 4]. It is composed of three subunits: the high-affinity IL-15 receptor subunit alpha (IL-15Rα), the IL-2/IL-15 receptor subunit beta (CD122), and the common cytokine receptor gamma chain (γc or CD132) [10, 11]. Signaling typically occurs via trans-presentation, where IL-15 is presented by IL-15Rα on the surface of one cell to the βγc signaling dimer on an adjacent lymphocyte, activating the JAK1/JAK3 and STAT3/STAT5 pathways [7, 10]. In oncology, IL-15 receptor agonists and superagonists, such as nogapendekin alfa inbakicept, are employed to stimulate anti-tumor immune responses by expanding effector cell populations [2, 9]. Conversely, antagonists and antibodies targeting the receptor subunits are under investigation for treating autoimmune and inflammatory conditions, such as rheumatoid arthritis and celiac disease, where excessive IL-15 signaling contributes to pathogenesis [1, 5]. Key therapeutic challenges include managing systemic toxicities like cytokine release syndrome and ensuring the selective activation of cytotoxic cells over regulatory T cells [12, 14].

Other names

IL-15 receptorIL-15R complexCD215/CD122/CD132 complexInterleukin-15 receptor subunit alpha/beta/gamma complexCommon gamma chain receptor complex

Agonism of the receptor complex leads to the activation of the JAK-STAT signaling pathway (specifically JAK1/JAK3 and STAT3/STAT5), promoting the expansion and cytotoxic activity of NK cells and CD8+ memory T cells [7, 11]. Antagonism involves blocking the interaction between IL-15 and its receptor subunits to dampen pathological immune responses in autoimmune and inflammatory conditions [1, 5].